Current Medicinal Chemistry - Volume 26, Issue 33, 2019

Background: Inherent or acquired chemo resistance in cancer patients has been a perpetual limitation in cancer treatment. Expanding knowledge on essential cellular processes opens a new window for therapeutic targeting. Ribosome biogenesis is a process that shows potential due to its fundamental role in cell development and contribution to tumorigenesis as a result of its upregulation. Inhibiting components of ribosome biogenesis has been explored and has shown interesting results. Yet, an important key component, methyltransferase Fibrillarin (FBL), which influences both the abundance and composition of ribosomes, has not been exploited thus far. Methods: In this literature review, we describe relevant aspects of ribosome biogenesis in cancer to emphasize the potential of FBL as a therapeutic target, in order to lower the genotoxic effects of anti-cancer treatment. Results: Remarkably, the amplification of the 19q13 cytogenetic band, including the gene coding for FBL, correlated to cell viability and resistance in pancreatic cells as well as to a trend toward a shorter survival in pancreatic cancer patients. Targeting ribosome biogenesis, more specifically compared to the secondary effects of chemotherapeutics such as 5-fluorouracil or oxaliplatin, has been achieved by compound CX-5461. The cell dependent activity of this Pol I inhibitor has been reported in ovarian cancer, melanoma and leukemia models with active or mutated p53 status, presenting a promising mechanism to evade p53 resistance. Conclusion: Targeting critical ribosome biogenesis components in order to decrease the genotoxic activity in cancer cell looks promising. Hence, we believe that targeting key protein rRNA methyltransferase FBL shows great potential, due to its pivotal role in ribosome biogenesis, its correlation to an improved survival rate at low expression in breast cancer patients and its association with p53.

Background: The possibilities of treatment for oncological diseases are growing enormously in the last decades. Unfortunately, these developments have led to the onset of resistances with regards to the new treatments. This is particularly true if we face with the therapeutic field of Tyrosine Kinase Inhibitors (TKIs). This review gives an overview of possible TKI resistances that can occur during the treatment of an oncologic diesease and available strategies that can be adopted, taking cues from a successful example such as CML. Methods: We performed a literature search for peer-reviewed articles using different databases, such as PubMed and Scopus, and exploiting different keywords and different logical operators. Results: 68 papers were included in the review. Twenty-four papers give an overview of the causes of TKIs resistances in the wide oncologic field. The remaining papers deal CML, deeply analysing the TKIs Resistances present in this pathology and the strategies adopted to overcome them. Conclusion: The aim of this review is to furnish an overview and a methodological guideline for the approach and the overcoming of TKIs Resistances.

The Androgen Receptor (AR) pathway plays a major role in both the pathogenesis and progression of prostate cancer. In particular, AR is chiefly involved in the development of Castration-Resistant Prostate Cancer (CRPC) as well as in the resistance to the secondgeneration AR antagonist enzalutamide, and to the selective inhibitor of cytochrome P450 17A1 (CYP17A1) abiraterone. Several small molecules acting as AR antagonists have been designed and developed so far, also as a result of the ability of cells expressing this molecular target to rapidly develop resistance and turn pure receptor antagonists into ineffective or event detrimental molecules. This review covers a survey of most promising classes of non-steroidal androgen receptor antagonists, also providing insights into their mechanism of action and efficacy in treating prostate cancer.

Background: Dual-targeting in cancer treatment by a single drug is an unconventional approach in relation to drug combinations. The rationale for the development of dualtargeting agents is to overcome incomplete efficacy and drug resistance frequently present when applying individual targeting agents. Consequently, -a more favorable outcome of cancer treatment is expected with dual-targeting strategies. Methods: We reviewed the literature, concentrating on the association between clinically relevant and/or novel dual inhibitors with the potential to modulate multidrug resistant phenotype of cancer cells, particularly the activity of P-glycoprotein. A balanced analysis of content was performed to emphasize the most important findings and optimize the structure of this review. Results: Two-hundred and forty-five papers were included in the review. The introductory part was interpreted by 9 papers. Tyrosine kinase inhibitors’ role in the inhibition of Pglycoprotein and chemosensitization was illustrated by 87 papers. The contribution of naturalbased compounds in overcoming multidrug resistance was reviewed using 92 papers, while specific dual inhibitors acting against microtubule assembling and/or topoisomerases were described with 55 papers. Eleven papers gave an insight into a novel and less explored approach with hybrid drugs. Their influence on P-glycoprotein and multidrug resistance was also evaluated. Conclusion: These findings bring into focus rational anticancer strategies with dual-targeting agents. Most evaluated synthetic and natural drugs showed a great potential in chemosensitization. Further steps in this direction are needed for the optimization of anticancer treatment.

Background: Porous micro- and nanoparticles have the capacity to encapsulate a large quantity of therapeutics, making them promising delivery vehicles for a variety of applications. This review aims to highlight the latest development of inorganic and hybrid (inorganic/ organic) particles for drug delivery with an additional emphasis on combatting drug resistant cancer. We go one step further and discuss delivery applications beyond medicinal delivery, as there is generally a translation from medicinal delivery to botanic delivery after a short lag time. Methods: We undertook a search of relevant peer-reviewed publications. The quality of the relevant papers was appraised using standard tools. The characteristics of the papers are described herein, and the relevant material and therapeutic properties are discussed. Results: We discuss 4 classes of porous particles in terms of drug delivery and theranostics. We specifically focus on silica, calcium carbonate, metal-phenolic network, and metalorganic framework particles. Other relevant biomedically relevant applications are discussed and we highlight outstanding therapeutic results in the relevant literature. Conclusion: The findings of this review confirm the importance of studying and utilizing porous particles for therapeutic delivery. Moreover, we show that the properties of porous particles that make them promising for medicinal drug delivery also make them promising candidates for agro-industrial applications.

Cancer treatment still represents a formidable challenge, despite substantial advancements in available therapies being made over the past decade. One major issue is poor therapeutic efficacy due to lack of specificity and low bioavailability. The progress of nanotechnology and the development of a variety of nanoplatforms have had a significant impact in improving the therapeutic outcome of chemotherapeutics. Nanoparticles can overcome various biological barriers and localize at tumor site, while simultaneously protecting a therapeutic cargo and increasing its circulation time. Despite this, due to their synthetic origin, nanoparticles are often detected by the immune system and preferentially sequestered by filtering organs. Exosomes have recently been investigated as suitable substitutes for the shortcomings of nanoparticles due to their biological compatibility and particularly small size (i.e., 30-150 nm). In addition, exosomes have been found to play important roles in cell communication, acting as natural carriers of biological cargoes throughout the body. This review aims to highlight the use of exosomes as drug delivery vehicles for cancer and showcases the various attempts used to exploit exosomes with a focus on the delivery of chemotherapeutics and nucleic acids.

Catalpol, a famous molecule of iridoids, possesses extensive pharmacological activities. Our studies found that compounds with low-polarity substituents at the 6-O position of catalpol exhibited higher NF-ΚB inhibitory potency than catalpol. However, catalpol derivatives are not much focused. Here this review provides extensive coverage of naturally occurring catalpol derivatives discovered from 1888 until 2018. It covers their distribution, chemotaxonomic significance, chemical structures, and bioactivities from more than 200 peer-reviewed articles, and highlights the structure-activity relationship of catalpol derivatives.

Background: Stroke is a major cause of mortality and disability in modern societies. Statins are effective medications in decreasing cardiovascular events through lipid lowering and pleiotropic effects. Objective: To summarize current evidence regarding the role of statins in the prevention and management of stroke. Methods: A narrative review of current evidence regarding the effect of statins in stroke management. Electronic searches of MEDLINE, EMBASE and Cochrane Databases were performed. Results: In primary prevention of stroke in patients with risk factors but no established cardiovascular disease, potent statins such as atorvastatin and rosuvastatin have shown some benefits, but the clinical relevance of this effect is questionable. In populations at higher risk of stroke, such as patients with established coronary heart disease, the majority of relevant studies have shown a beneficial effect of statins in preventing stroke. Similarly, in patients with a previous cerebrovascular event, there is a clear benefit of statins for the prevention of recurrent events. The use of statins is not associated with an increased risk of intracranial bleeding in primary prevention studies. There may be an increased incidence of non-fatal hemorrhagic stroke with high dose statins in patients with a previous cerebrovascular event. Patients who experience a stroke while on statins should not discontinue statins. In addition, statins are associated with better survival and improved functional outcome when administered during the acute phase of stroke in statin-naive patients. In contrast, statins do not confer any benefit in patients with acute ischemic stroke who receive thrombolysis. Conclusion: Treatment with statins prevents ischemic stroke, especially in patients with high cardiovascular risk and established atherosclerotic disease. It seems that both lipid lowering and pleiotropic effects contribute to these effects.